Mood disorders in late-life may be early warning signs for dementia

Depression and bipolar disorder of late onset may represent more than just mental health conditions. Growing evidence suggests these late-life mood disorders (LLMDs) could be not merely risk factors, but rather early warning signs of neurodegenerative diseases like dementia, even when they appear years before memory loss or other cognitive symptoms become apparent.

Unfortunately, scientists have struggled to understand the connection between LLMDs and developing dementia at the biological level. While previous research suggested connections between specific disorders like late-life depression and Alzheimer’s disease, the specific neurological mechanisms involved remain mostly unclear. This knowledge gap is particularly pronounced for late-life bipolar disorder, which has rarely been investigated in relation to dementia. On top of this, limitations in brain imaging technology have prevented researchers from detecting all the different types of abnormal proteins that might underlie these conditions.

Against this backdrop, a research team led by Dr. Shin Kurose and Dr. Keisuke Takahata from the National Institutes for Quantum Science and Technology (QST), Japan, conducted a comprehensive investigation into the brain changes associated with LLMDs. Their paper, published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association on June 09, 2025, explores the presence of abnormal tau protein—a hallmark of several neurodegenerative diseases—in the brains of people with late-life depression and bipolar disorder. The study was co-authored by Dr. Makoto Higuchi, also from QST, and Dr. Masaki Takao from the National Center of Neurology and Psychiatry.

The researchers used advanced brain imaging techniques to examine 52 participants with LLMDs and 47 healthy controls. They employed a positron emission tomography (PET) scan using two different tracers, which can detect various forms of tau protein and amyloid beta accumulation, key proteins associated with Alzheimer’s disease, and other neurodegenerative diseases. To validate their findings, they also analyzed brain tissue samples from 208 autopsy cases, examining the relationship between late-life mood symptoms and the subsequent development of neurodegenerative diseases.

The results were striking: Approximately 50% of participants with LLMDs showed tau accumulation in their brains, compared to only about 15% of healthy controls. Similarly, nearly 29% of participants with LLMDs had detectable amyloid deposits versus just 2% of controls. The autopsy findings further supported these results, showing a significantly higher prevalence of diverse tau protein-related pathologies in individuals who had experienced late-life mania or depression. “Because most of the participants with LLMDs in our study had no or mild cognitive decline, these results support the evidence that neurodegenerative diseases, including Alzheimer’s and non-Alzheimer’s tau-related pathologies, can initially manifest as psychiatric symptoms,” highlights Dr. Kurose.

Another noteworthy discovery was that many participants showed tau accumulation in the frontal regions of the brain, which is crucial for emotional regulation and cognitive function. The study also revealed that these abnormal proteins could be detected years before traditional cognitive symptoms of dementia appeared. As revealed by the autopsy cases, mood symptoms preceded cognitive or motor symptoms by an average of 7.3 years. “Overall, our findings strongly suggest that tau-PET scans can detect diverse tau pathologies that underlie dementia in patients with LLMDs,” concluded Dr. Takahata.

The insights uncovered in this study have important implications for clinical practice, as some cases of late-life depression and bipolar disorder could likely benefit from an evaluation for underlying neurodegenerative diseases. Timely identification of these conditions would allow for earlier intervention with disease-modifying treatments. Moreover, the researchers also highlight the value of the tracer molecules used in their PET scans as effective biomarkers for detecting these diverse tau-related pathologies in living patients.

With any luck, these efforts will help solidify our understanding of how neurodegenerative diseases first manifest, leading to earlier diagnosis and potentially better outcomes.

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Reference
DOI: 10.1002/alz.70195

About National Institutes for Quantum Science and Technology, Japan
The National Institutes for Quantum Science and Technology (QST) was established in April 2016 to promote quantum science and technology in a comprehensive and integrated manner. The new organization was formed from the merger of the National Institute of Radiological Sciences (NIRS) with certain operations that were previously undertaken by the Japan Atomic Energy Agency (JAEA).

QST’s mission is to raise the level of quantum and radiological sciences and technologies through its commitment to research and development into quantum science and technology, the effect of radiation on humans, radiation emergency medicine, and the medical use of radiation.

To ensure that research and development delivers significant academic, social and economic impacts, and to maximize benefits from global innovation, QST is striving to establish world-leading research and development platforms, explore new fields, and serve as a center for radiation protection and radiation emergency medicine.

Website: https://www.qst.go.jp/site/qst-english/

About Dr. Shin Kurose from National Institutes for Quantum Science and Technology, Japan
Dr. Shin Kurose joined the Department of Functional Brain Imaging Research at QST as a pre-doctoral researcher in 2021. His background is clinical neuropsychiatry and is now training in neuropathology as a postdoctoral fellow. He is interested in clinico-imaging-pathological correlations in neuropsychiatry.

About Dr. Keisuke Takahata from National Institutes for Quantum Science and Technology, Japan
Dr. Keisuke Takahata joined the Department of Functional Brain Imaging Research at QST as a Researcher in 2017. He specializes in using PET imaging to study delayed neurodegeneration due to traumatic brain injury and neurodegenerative diseases associated with late-life psychiatric disorders. He has over 140 scientific publications to his name.

Funding information
This study was supported by a Grant-in-Aid for Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS; JP19dm0207072), Strategic International Brain Science Research Promotion Program (Brain/MINDS Beyond; JP19dm0307105), Japan Science and Technology Agency (JST; JPMJMS2024), and the Japan Agency for Medical Research and Development (AMED; JP24wm0625001, JP24zf0127012 and Brain/MINDS 2.0: JP24wm0625304) awarded to Makoto Higuchi; the Research Program on Emerging and Re-emerging Infectious Diseases of AMED (JP25fk0108707), Japan Society for the Promotion of Science (JSPS; 20K07935, 24K02374), and Astellas Foundation for Research on Metabolic Disorders awarded to Keisuke Takahata; Intramural fund from NCNP (Grant Number: 3-8, 6-5, 6-8), AMED (JP21wm0425019), JSPS (21K06417, 22H04923, 24K02374, 23H00414) awarded to Masaki Takao; JSPS (24K02379) awarded to Hidehiko Takahashi; JSPS (22H02998) to Manabu Kubota; AMED JP22dk0207055 to Takahiko Tokuda; JP24wm0625505 to Kenji Tagai.